Biomarkers of Mineralocorticoid Receptor Activation

a mineralocorticoid receptor and biomarker technology, applied in the field of biomarkers of the mineralocorticoid receptor activation, can solve the problems of serious adverse side effects of mr antagonist administration in a patient, and the effect of mr activation in the cardiovascular system may occur,

Inactive Publication Date: 2011-10-20
INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM) +2
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Deleterious effects of MR activation in the cardiovascular system may thus occur even in the absence of hyperaldosteronism (Funder J W, 2006) and plasma levels of aldosterone do not provide in

Method used

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  • Biomarkers of Mineralocorticoid Receptor Activation
  • Biomarkers of Mineralocorticoid Receptor Activation
  • Biomarkers of Mineralocorticoid Receptor Activation

Examples

Experimental program
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example 1

[0116]MR and GR transgenic mice: Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) transgenic mice allowed conditional expression of the human MR or GR, respectively. MR and GR transgenic mice were obtained by breeding the in-house generated acceptor mice that allowed conditional, inducible expression of hMR or hGR when crossed with appropriate transactivator mice. These conditional transgenic models have been described in Ouvrard-Pascaud et al. (2005) and Sainte-Marie et al. (2007). To identify genes selectively modulated by MR in the heart, the MR and GR acceptor mice were crossed with the MHC-tTA transactivator mice provided by G. Fishman, Columbia University, NY, USA) (Yu et al. 1996) allowing cardiomyocyte-specific expression of hMR and hGR, respectively. This resulted in 4 fold overexpression of MR or 3 fold increase glucocorticoid binding in the heart of MR or GR conditional mice, respectively, as compared to control littermates. To avoid early embryonic lethal...

example 2

[0134]The plasma level of Lcn2 / NGAL has been measured in a population of healthy subjects.

[0135]Men and women aged between 18 and 85 years-old were included in the study, provided that they had presented no acute pathology in the past 7 days and were not under any cardiovascular treatment. Further exclusion criteria for healthy controls were: known high blood pressure (greater than 140 / 90 mmHg or greater than 160 mm Hg if older than 65); known renal failure, known diabetes, pregnancy, cancer diagnosed within the past 5 years or evolutive neoplasia, chronic liver pathology, connectivitis, Crohn's disease, evolutive tuberculosis, exertional angina, acute coronarien syndrome, history of coronopathy, carotidien endarterectomy and known abdominal aortic aneurysm.

[0136]The plasma level of Lcn2 / NGAL of the healthy subjects was generally comprised between 40 and 80 μg / ml.

[0137]The plasma level of Lcn2 / NGAL of patients affected with a cardiovascular disease, diabetes, obesity or metabolic sy...

example 3

[0138]Chronic overexpression of MR or GR in cardiomyocytes may lead to altered signaling pathways, representing adaptations of the cells, different from those induced by short-term corticosteroid treatment. To analyze the molecular consequences of chronic MR activation in vivo in the heart, we investigated cardiac gene expression of MR-cardiac mice using Cardiochips®, i.e. microarrays including 5419 genes that had been selected for their involvement in cardiovascular and / or skeletal muscle normal and pathological functioning. Cardiomyocyte MR overexpression for 6 weeks resulted in about 24 up-regulated and 23 down-regulated genes. Interestingly, most of them differed from GR-regulated genes that were determined in parallel in GR-cardiac mice (about 74 GR up-regulated genes and 70 GR down-regulated genes). Moreover, most of the MR-regulated genes did not change in the GR-cardiac mouse model, indicating that each steroid receptor controls a distinct pattern of gene expression in cardi...

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Abstract

The present invention relates to the use of Neutrophil Gelatinase-Associated Lipocalin (NGAL) and/or SERPINA3 as biomarkers of the Mineralocorticoid Receptor (MR) activation in a patient. More particularly, the present invention relates to a method for predicting the responsiveness of a patient to a treatment with a MR antagonist or an aldosterone synthase inhibitor, said method comprising determining in a biological sample obtained from said patient the expression level of the NGAL gene and/or of the SERPINA3 gene.

Description

FIELD OF THE INVENTION[0001]The present invention relates to biomarkers of the Mineralocorticoid Receptor (MR) activation in a patient.BACKGROUND OF THE INVENTION[0002]Mineralocorticoid receptor (MR) is a member of the classic steroid hormone receptors that include glucocorticoid receptor (GR), androgen receptor (AR), progesterone receptor (PR), and estrogen receptor (ER) (Funder, 1997). These receptors are hormone-activated transcriptional factors that regulate a wide variety of physiological processes ranging from organ development and differentiation to mood control and stress response (Beato et al., 1995). The physiological hormone for MR is aldosterone which is a steroid hormone secreted by the adrenal gland.[0003]MRs have been located on non-epithelial sites in blood vessels, brain, and heart (Bonvalet J P. et al. 1995; Lombes M, et al. 1992; Tanaka J. et al. 1997). Numerous studies over the past 10 years suggest that the non-epithelial actions of mineralocorticoids are respon...

Claims

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Application Information

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IPC IPC(8): A61K31/585G01N33/566A61P3/00A61P9/00A61P3/10A61P3/04C12Q1/68A61K31/5685
CPCC12Q1/6883C12Q2600/158G01N33/6893C12Q2600/106G01N2800/321G01N2800/325G01N2800/52G01N2800/32A61P3/00A61P3/04A61P43/00A61P9/00A61P9/10A61P3/10G01N33/6803G01N2800/04G01N2800/042G01N2800/044
Inventor JAISSER, FREDERICFARMAN, NICOLETTESAINTE-MARIE, YANNISLATOUCHE, CELINESTEENMAN, MARJA
Owner INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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